The oncogenic role of SAMMSON lncRNA in tumorigenesis: A comprehensive review with especial focus on melanoma.

LncRNA Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON) is located on human chromosome 3p13, and its expression is upregulated in several tumours, including melanoma, breast cancer, glioblastoma and liver cancer and has an oncogenic role in malignancy disorders. It has been reported that SAMMSON impacts metabolic regulation, cell proliferation, apoptosis, EMT, drug resistance, invasion and migration. Also, SAMMSON is involved in regulating several pathways such as Wnt, MAPK, PI3K, Akt, ERK and p53. SAMMSON is considered a potential diagnostic and prognostic biomarker in several types of cancer and a suitable therapeutic target. In addition, the highly expressed SAMMSON is closely associated with clinicopathological features of various cancers. SAMMSON has a significant role in regulating epigenetic processes by regulating histone protein or the status of DNA methylation. Herein for the first time, we comprehensively summarized the currently available SAMMSON, molecular regulatory pathways, and clinical significance. We believe that clarifying all the molecular aspects of this lncRNA can be a good guide for cancer studies in the future.

Cardioprotective effect of tamoxifen and raloxifene: Preventing proteoglycan synthesis by modulating non-canonical TGF-ß signalling through NADPH oxidase and ERK phosphorylation.

Atherosclerosis, a leading cause of cardiovascular disease, remains a significant global health concern. Tamoxifen and raloxifene, selective estrogen receptor modulators (SERMs), have demonstrated potential cardioprotective effects. However, the underlying molecular mechanisms by which these SERMs modulate Transforming Growth Factor-ß (TGF-ß) signaling in human vascular smooth muscle cells (VSMCs) remain largely unexplored. This study sought to investigate the impact of tamoxifen and raloxifene on TGF-ß-induced CHSY1 expression and Smad2 linker region phosphorylation in VSMCs and to elucidate the role of reactive oxygen species (ROS), NADPH oxidase (NOX), and kinase pathways in mediating these effects. Employing a comprehensive experimental strategy, VSMCs were treated with TGF-ß in the presence or absence of tamoxifen, raloxifene, and various pharmacological inhibitors. Subsequently, CHSY1 mRNA expression, Smad2C and Smad2L phosphorylation, ROS production, p47phox and ERK 1/2 phosphorylation were assessed. Our results revealed that tamoxifen and raloxifene significantly attenuated TGF-ß-mediated CHSY1 mRNA expression and Smad2 linker region phosphorylation, without affecting the canonical TGF-ß-Smad2C pathway. Furthermore, these compounds effectively inhibited ROS production, p47phox and ERK 1/2 phosphorylation, implicating the involvement of the TGF-ß-NOX-ERK-Smad2L signaling cascade in their cardioprotective properties. This study provides a comprehensive understanding of the molecular mechanisms underlying the cardioprotective effects of tamoxifen and raloxifene in VSMCs, offering valuable insights for the development of targeted therapeutic strategies aimed at atherosclerosis prevention and the promotion of cardiovascular health.

Impact of modifiable risk factors on prediction of 10-year cardiovascular disease utilizing framingham risk score in Southwest Iran.

BACKGROUND: This cohort study was conducted to examine the association between modifiable risk factors, including hypertension, smoking, physical activity, diabetes, cholesterol, and high-density lipoprotein with Framingham risk score in the prediction of 10-year-risk of cardiovascular diseases (CVD) between men and women in an Arab community of Southwest Iran, Hoveyzeh. MATERIALS AND METHODS: A total of 8,526 people aged 35-70 participated in this cohort study. Framingham was used to estimate the 10-year risk of CVD. Also, the linear regression models were used to assess the relationship between modifiable risk factors and the 10-year risk of CVD. Finally, the area under the receiver operating characteristic curve (AUC) was used to measure the ability of modifiable risk factors to predict the 10-year risk of CVD. RESULTS: Our results of linear regression models showed that hypertension, smoking, PA, diabetes, cholesterol, and HDL were independently associated with the CVD risk in men and women. Also, AUC analysis showed that hypertension and diabetes have the largest AUC in men 0.841; 0.778 and in women 0.776; 0.715, respectively. However, physical activity had the highest AUC just in women 0.717. CONCLUSION: Hypertension and diabetes in both gender and physical activity in women are the most important determinant for the prediction of CVD risk in Hoveyzeh. Our cohort study may be useful for adopting strategies to reduce CVD progression through lifestyle changes.

Endothelin-1 mediated glycosaminoglycan synthesizing gene expression involves NOX-dependent transactivation of the transforming growth factor-ß receptor.

G protein-coupled receptor (GPCR) agonist endothelin-1 (ET-1) through transactivation of the transforming growth factor (TGF) ß receptor (TGFBR1) stimulates glycosaminoglycan (GAG) elongation on proteoglycans. GPCR agonists thrombin and lysophosphatidic acid (LPA) via respective receptors transactivate the TGFBR1 via Rho/ROCK dependent pathways however mechanistic insight for ET-1 transactivation of the TGFBR1 remains unknown. NADPH oxidase (NOX) generates reactive oxygen species (ROS) and is a signalling entity implicated in the pathogenesis of many diseases including atherosclerosis. If implicated in this pathway, NOX/ROS would be a potential therapeutic target. In this study, we investigated the involvement of NOX in ET-1/ET receptor-mediated transactivation of TGFBR1 to stimulate mRNA expression of GAG chain synthesizing enzymes chondroitin 4-O-sulfotransferase 1 (C4ST-1) and chondroitin sulfate synthase 1 (ChSy-1). The invitro model used vascular smooth muscle cells that were treated with pharmacological antagonists in the presence and absence of ET-1 or TGF-ß. Proteins and phosphoproteins isolated from treated cells were quantified by western blotting and quantitative real-time PCR was used to assess mRNA expression of GAG synthesizing enzymes. In the presence of diphenyliodonium (DPI) (NOX inhibitor), ET-1 stimulated phospho-Smad2C levels were inhibited. ET-1 mediated mRNA expression of GAG synthesizing enzymes C4ST-1 and ChSy-1 was also blocked by TGBFR1 antagonists, SB431542, broad spectrum ET receptor antagonist bosentan, DPI and ROS scavenger N-acetyl-L-cysteine. This work shows that NOX and ROS play an important role in ET-1 mediated transactivation of the TGFBR1 and downstream gene targets associated with GAG chain elongation. As ROS is involved in GPCR to protein tyrosine kinase receptor transactivation, the NOX/ROS axis presents as the first common biochemical target in all GPCR to kinase receptor transactivation signalling.

Methylation-mediated silencing of miR-125a-5p facilitates breast cancer progression by inducing autophagy.

BACKGROUND: microRNA-125a-5p (miR-125a) is a tumor suppressor gene whose role in autophagy remains poorly understood. In the current study, we aimed to investigate the methylation status of miR-125a, its transfection into SK-BR3 cells, and its effects on autophagy. METHODS: Sixty samples of tumor and non-tumor adjacent tissue were collected and the methylation status of miR-125a was evaluated by methylation-specific PCR (MSP). The effect of 5-Aza-dC on miR-125a expression was investigated in the SK-BR3 cells. Cells were also transfected with miR-125a mimic/antimiR. The expression of miR-125a and its target genes was evaluated by Real-Time PCR. Protein levels of ATG5 and LC3 were assessed by Western blotting. HER2 expression was investigated by immunocytochemistry (ICC). RESULTS: The data showed that the miR-125a promoter CpG Island was significantly hypermethylated in breast cancer tissues (p < 0.01) and in SK-BR3 cells. The 5-Aza-dC could significantly increase miR-125a expression by decreasing its methylation (p < 0.05). In addition, Western blot analysis indicated the expression of ATG5 and LC3 II/ LC3I, as autophagy biomarkers, was significantly reduced in SK-BR3 cells transfected with miR-125a (p < 0.05). CONCLUSIONS: Our data showed miR-125a expression was significantly decreased in tumor tissues due to its promoter hypermethylation. Overexpression of miR-125a was associated with a reduction in autophagy, which could provide a new therapeutic avenue for advanced-stage breast cancer treatment.

Bioaccumulation and health risk assessment of exposure to potentially toxic elements by consuming agricultural products irrigated with wastewater effluents.

Potentially toxic elements (PTEs) have many adverse health effects due to bioaccumulation capability and their long persistence in the environment. As a renewable water source, the effluents of municipal wastewater treatment systems have been used to irrigate agricultural products widely. However, the evidence on the bioaccumulation of PTEs in crops irrigated with these effluents is still scarce, with no available study in low and middle-income countries. Therefore, this study aimed to assess the PTEs concentration in the soil and crops irrigated with effluents of Sabzevar wastewater treatment plant and the related health risk by that. The clustered method was used to determine the soil and craps samples. Seventy cumulative samples were randomly prepared in summer and autumn 2016 and 2017 from crops, soil and effluent. Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure PTEs. The health risk of exposure to PTEs was assessed using Monte Carlo simulation technique. Kruskal Wallis test and Posthoc Tukey HSD test were used to assess the mean difference of PTEs between soil, effluent and crops as well as between crops together. The bioaccumulation factor (BAF) magnitude order in different crop samples was Cd > Sr > Cu > Pb > Zn > Co > As > Cr > Ni, respectively. The Cd accumulation in Sugar beet plant was significantly higher than in other samples. The highest hazard quotient (HQ) based on single PTEs was observed for As (mineral) (mean: 5.62 × 10-1 and percentile 95th: 2.13) in Okra. Regarding total HQ (THQ), the highest and lowest mean (percentile 95th) values were 1.50 (3.22) and 2.40 × 10-1 (4.01 × 10-1) for Okra and Watermelon, respectively. The mean concentrations of Co, Cr, Ni and Zn were significantly higher in crops compared to soil and influent samples. Posthoc tests indicated that the concentration of PTEs between investigated crop samples were not statistically significant different (p > 0.05). Overall, our study suggested that irrigation with the effluent of stabilization pond wastewater treatment system exerts a potential health risk due to bioaccumulation of PTEs in crops.

Endothelin-1 dependent expression of GAG genes involves NOX and p38 mediated Smad linker region phosphorylation.

Endothelin-1 (ET-1) is implicated in the development of atherosclerosis and mediates glycosaminoglycan (GAG) chain hyperelongation on proteoglycans. Our aim was to identify the ET-1-mediated signalling pathway involving NADPH oxidase (NOX), p38 MAP kinsae and Smad2 linker region phosphorylation (phospho-Smad2L) regulate GAG synthesising enzymes mRNA expression (C4ST-1 and ChSy1) involved in GAG chains hyperelongation in human vascular smooth muscle cells (VSMCs). Signalling intermediates were detected and quantified by Western blotting and the mRNA levels of GAG synthesising enzymes were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). ET-1 treatment of human VSMCs resulted in an increase in phospho-Smad2L level. The TGF-ß receptor antagonist, SB431542 and the mixed ETA and ETB receptor antagonist bosentan, inhibited ET-1-mediated phospho-Smad2L level. In the presence of apocynin and diphenyleneiodonium chloride (DPI) (NOX inhibitors) and SB239063 (p38 inhibitor) ET-1-mediated phospho-Smad2L levels were inhibited. The gene expression levels of GAG synthesising enzymes post-ET-1 treatment were increased compared to untreated controls (p < 0.01). The ET-mediated the mRNA levels of these enzymes were blocked by the bosentan, SB431542, SB239063, DPI, apocynin and antioxidant N-acetyl-L-cysteine (NAC). ET-1-mediated signalling to GAG synthesising enzymes gene expression occurs via transactivation-dependent pathway involving NOX, p38 MAP kinsae and Smad2 linker region phosphorylation.

Prenatal exposure to traffic-related air pollution and glucose homeostasis: A cross-sectional study.

Air pollution exposure has been linked with glucose dysregulation in pregnant women; however, evidence on these associations with fetal glucose homeostasis is unclear yet. We therefore aimed to evaluate the association of prenatal exposure to particulate matter (PM) and traffic indicators with fetal glucose homeostasis in cord blood samples. A total of 169 mother-infant pairs recruited from Mobini hospital of Sabzevar, Iran, were included in this cross-sectional study. Maternal exposure to PMs was estimated using land use regression models. Moreover, traffic indicators (i.e., total street length in 100, 300 and 500 m buffers and distance from residential home to the nearest major roads) were calculated based on the street map of Sabzevar. Cord blood glucose and insulin concentrations, HOMA-ꞵ, HOMA-S and HOMA-IR were used as glucose homeostasis markers. Higher maternal exposure to PM2.5 and PM10 were associated with higher cord blood glucose and insulin concentrations and HOMA-IR. Moreover, total streets length in 300 m buffer was positively associated with cord blood glucose and insulin concentrations and HOMA-IR. An increase in distance to major roads was associated with higher HOMA-ꞵ and HOMA-S and lower cord blood glucose and insulin concentrations as well as HOMA-IR. Overall, we found prenatal exposure to PMs and traffic indicators was associated with a higher risk of glucose homeostasis dysregulation in the fetus.

Comparing BTEX concentration related to surgical smoke in different operating rooms.

The available evidence on the indoor air quality of operating rooms (ORs) in the Low- and Middle-income Countries (LMICs) is very scarce. Moreover, there is no study on the comparing the concentration of indoor air pollutants in different ORs. Therefore, this study aimed to measure and compare the benzene, toluene, ethylbenzene and xylene (BTEX) concentrations in the air of different ORs in hospitals of Sabzevar, Iran. Moreover, carcinogenic and non-carcinogenic risk of exposure to these pollutants were assessed using Monte Carlo simulations technique. This cross-sectional study was based on volatile organic compounds (VOCs) passive sampling of eight ORs including General surgery, Curettage, Eye surgery, Neurosurgery, Orthopedic, Laparoscopic, Cesarean and Ear, nose, throat (ENT) in two monthly campaigns from November 2019 to February 2020. One-way ANOVA and Post-hoc analyses were used to compare the concentration of BTEX compounds in different ORs. The overall mean (standard deviation (SD)) of benzene, toluene, ethylbenzene, xylene and total BTEX concentrations were 10.0 (1.8), 7.2 (1.9), 1.8 (0.6), 0.4 (0.2) and 19.4 (4.1) µg/m3. The Curettage OR had the highest (12.93 µg/m3) and ENT OR had the lowest (7.42 µg/m3) benzene concentrations. The highest concentrations of toluene, ethylbenzene and total BTEX were observed in General surgery OR. The cancer risks of exposure to benzene in all ORs were higher than the acceptable range recommended by Unite State Environmental Protection Agency (USEPA, 1 × 106). However, the hazard quotient (HQ) values for all ORs were at safe level (HQ < 1). Overall, our study suggested that the concentrations of BTEX compounds were significantly difference in different ORs and benzene had a carcinogenic risk for personnel and surgical staff in different ORs.

Poly-phosphate increases SMC differentiation of mesenchymal stem cells on PLGA-polyurethane nanofibrous scaffold.

The use of bioactive scaffolds in tissue engineering has a significant effect on the damaged tissue healing by an increase in speed and quality of the process. Herein, electrospinning was applied to fabricate composite nanofibrous scaffolds by Poly lactic-co-glycolic acid (PLGA) and Polyurethane (PU) with and without poly-phosphate (poly-P). Scaffolds were characterized morphologically by scanning electron microscope (SEM), and their biocompatibility was also investigated by SEM, protein adsorption, cell attachment and survival assays. The applicability of the scaffolds for bladder tissue engineering was also evaluated by culturing mesenchymal stem cells (MSCs) on the scaffolds and their differentiation into smooth muscle cell (SMC) was studied at the gene and protein levels. The results demonstrated that scaffold biocompatibility was increased significantly by loading poly-P. SMC related gene and protein expression level in MSCs cultured on poly-P-loaded scaffold was also increased significantly compared to those cells cultured on empty scaffold. It can be concluded that poly-P hasn't also increased scaffold biocompatibility, but also SMC differentiation potential of MSCs was also increased while cultured on the poly-P containing scaffold compared to the empty scaffold. Taken together, our study showed that PLGA-PU-poly-P alone and in combination with MSCs has a promising potential for support urinary bladder smooth muscle tissue engineering.

Combination of Silibinin and Curcumin Reduced Leptin Receptor Expression in MCF-7 Human Breast Cancer Cell Line.

BACKGROUND: Leptin and leptin receptor (Ob-R) are associated with worse prognosis, distant metastasis, and poor survival of breast cancer. We investigated the cytotoxic effect of silibinin and curcumin, individually and combined, on Ob-R expression in MCF-7 cells. METHODS: This study was performed from October 2017 to April 2018 at the Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. The cytotoxic effect of silibinin and curcumin, individually and combined, and their corresponding half-maximal inhibitory concentration (IC50) values were determined using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. The cells were treated with different concentrations of silibinin (50-400 µM), curcumin (10-35 µM), and their combinations for 24 and 48 hours. The expression of Ob-R was measured using the Western blot analysis by treating the cells with different concentrations of curcumin (10-25 µM), silibinin (50-250 µM), and their respective combinations. The difference in mean cell viability between the groups was calculated using one-way ANOVA followed by Tukey's post hoc test. RESULTS: Silibinin and curcumin exerted time- and dose-dependent cytotoxic effect on MCF-7 cells. After treatment with silibinin, the IC50 values were about 250 and 50 µM at 24 and 48 hours, respectively. In terms of treatment with curcumin, the IC50 values were about 25 and 15 µM at 24 and 48 hours, respectively. Following treatment with silibinin, the Western blot analysis showed that Ob-R expression significantly decreased at 150 µM (P=0.031) and 200 µM (P=0.023) concentrations. Curcumin did not significantly decrease the Ob-R expression, however, the expression significantly decreased (P=0.004) when it was combined with silibinin. CONCLUSION: The combination of silibinin and curcumin significantly reduced Ob-R expression in MCF-7 cells compared with their individual effects.

Signaling Crosstalk of FHIT, p53, and p38 in etoposide-induced apoptosis in MCF-7 cells.

Fragile histidine trail (FHIT) is a tumor suppressor in response to DNA damage which has been deleted in various tumors. However, the signaling mechanisms and interactions of FHIT with regard to apoptotic proteins including p53 and p38 in the DNA damage-induced apoptosis are not well described. In the present study, we used etoposide-induced DNA damage in MCF-7 as a model to address these crosstalks. The time course study showed that the expression of FHIT, p53, and p38MAPK started after 1 hour following etoposide treatment. FHIT overexpression led to increase p53 expression, p38 activation, and augmented apoptosis following etoposide-induced DNA damage compared to wild-type cells. However, FHIT knockdown blocked p53 expression, delayed p38 activation, and completely inhibited etoposide-induced apoptosis. Inhibition of p38 activity prevented induction of p53, FHIT, and apoptosis in this model. Thus, activation of p38 upon etoposide treatment leads to increase in FHIT and p53 expression. In p53 knockdown MCF-7, the FHIT induction was hampered but p38 activation was induced in lower doses of etoposide. In p53 knockdown cells, inhibition of p38 induced FHIT expression and apoptosis. Our data demonstrated that the exposure of MCF-7 cells to etoposide increases apoptosis through a mechanism involving the activation of the p38-FHIT-p53 pathway. Moreover, our findings suggest signaling interaction for these pathways may represent a promising therapy for breast cancer.

Luteolin confers renoprotection against ischemia-reperfusion injury via involving Nrf2 pathway and regulating miR320.

This work aims to evaluate the renoprotective effect of luteolin on expression of Nrf2 and miR320 in ischemia-reperfusion (I/R) injury in rats. Thirty rats were randomly divided into five groups; control, Luteolin (50 mg/kg), ischemia-reperfusion (I/R), DMSO (0/1%) + I/R and Luteolin+I/R, (n = 6 each). Administration of luteolin and DMSO was carried out by gavage for 3 days before renal I/R. Then, the rats were subjected to bilateral renal ischemia for 45 min and followed by reperfusion for 2 h. All rats were killed and the renal function, histological changes, oxidative stress degree, in all of groups were evaluated. In addition, the effects of luteolin on renal expression of Nrf2 and miR320 were examined by immunohistochemistry and real time- PCR. Luteolin significantly improved the creatinine (Cr) and blood urea nitrogen (BUN) levels in Luteolin + I/R group compared to I/R group (p < 0.001 and p < 0.001 respectively). Reduction of enzymatic activity of superoxide dismutase, glutathione peroxidase and catalase in I/R and DMSO + I/R groups, was significantly improved by Luteolin (p < 0.05) in Luteolin + I/R group. Pre-treatment with luteolin also resulted in significant reduction in tissue MDA level (p < 0.001), Nrf2 (p < 0.001) and miR320 expression (P < 0.05) that were increased by renal I/R. Also, the rats pretreated with luteolin had nearly normal structure of the kidney. These results indicate that luteolin protects the kidney against I/R injury via reducing oxidative stress, increasing antioxidant enzymes and reducing expression of Nrf2 and miR320.

Ecological and health risk assessment of exposure to atmospheric heavy metals.

In the present study, we assessed the concentration of airborne HMs (Zn, Cu, Pb, and Cd) and their probable sources using the bark of Pinus eldarica as a bio-indicator. Hence, 47 tree bark samples were harvested according to the land uses and biomonitoring techniques in the city of Yazd, Iran. The potential health risks in 13 age groups, ecological risk, as well as the possible relationship between HM concentrations and traffic indicators, were evaluated. The order of average HM concentrations in the P. eldarica bark samples was as Zn > Pb > Cu > Cd. The mean values of non-carcinogenic risks of all HMs in entire age groups were within secure range (HQ < 1); however, the carcinogenic risk of Cd was higher than the allowed level (TCR > 1 × 10-6). About Pb, it was in the safe level. The main element causing potential ecological risks was Cd, indicating moderate to very high ecological risk in most of the study areas. There was an inverse significant association between distance from major roads and Pb concentration (ß = -0.011 95% confidence interval (CI): 0.022, -0.0001). All HMs in bark samples render the negative Moran's index, representing a random spatial distribution pattern. Besides, according to principal component analysis (PCA), the first component accounted for 36.55% of the total variance, dominated by Cd, Pb, Cu, and Zn, respectively, and characterized by vehicle and industrial emissions. Our results infer that industrial activities and traffic are the main sources of HMs pollution in urban environments that should be considered by decision-makers.

Reactive Oxygen Species and p38MAPK Have a Role in the Smad2 Linker Region Phosphorylation Induced by TGF-ß.

Background: Transforming growth factor-ß (TGF-ß) in addition to the C-terminal region can phosphorylate receptor-regulated Smads (R-Smads) in their linker region. The aim of the present study was to evaluate the role of signaling mediators such as NAD(P)H oxidases (reactive oxygen species [ROS] generators), ROS, and ROS-sensitive p38 mitogen-activated protein kinase (p38MAPK) in this signaling pathway in cultured human vascular smooth muscle cells (VSMCs). Methods: The present in vitro study was performed on human VSMCs. Proteins were detected by western blotting utilizing an anti-phospho-Smad2 (Ser245/250/255) rabbit polyclonal antibody and a horseradish peroxidase-labeled secondary antibody. Glyceraldehyde-3-phosphate dehydrogenase was used as a loading control. The phospho-Smad2 linker region (pSmad2L) was detected in all the experimental groups: a control group (untreated group), a group treated with TGF-ß (2 ng/mL), and a group treated with TGF-ß plus different inhibitors. The data were normalized and presented as mean±SEM. The statistical analyses were performed using SPSS, version 16.0, and the nonparametric Kruskal-Wallis test. A P value smaller than 0.05 was considered statistically significant. Results: The VSMCs treated with TGF-ß (2 ng/mL) showed a time-dependent increase in the pSmad2L level. The highest level was observed at 15 minutes (P=0.03). The inhibitors of NAD(P)H oxidases (diphenyleneiodonium and apocynin) (P=0.04), ROS scavenger (N-acetylcysteine) (P=0.04), and p38MAPK inhibitor (SB-202190) (P=0.04) were able to reduce the increased level of the pSmad2L by TGF-ß. Conclusion: Our results suggested that NAD(P)H oxidases played an important role in the Smad2L phosphorylation in the human VSMCs. Furthermore, our results confirmed that ROS and p38MAPK were involved in this signaling pathway. Thus, TGF-ß via a ROS-dependent mechanism can transmit its signals to the pSmad2L.

Peptidyl-prolyl isomerases: functionality and potential therapeutic targets in cardiovascular disease.

Peptidyl-prolyl cis/trans isomerases (PPIases) are a conserved group of enzymes that catalyse the conversion between cis and trans conformations of proline imidic peptide bonds. These enzymes play critical roles in regulatory mechanisms of cellular function and pathophysiology of disease. There are three different classes of PPIases and increasing interest in the development of specific PPIase inhibitors. Cyclosporine A, FK506, rapamycin and juglone are known PPIase inhibitors. Herein, we review recent advances in elucidating the role and regulation of the PPIase family in vascular disease. We focus on peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an important member of the PPIase family that plays a role in cell cycle progression, gene expression, cell signalling and cell proliferation. In addition, Pin1 may be involved in atherosclerosis. The unique role of Pin1 as a molecular switch that impacts on multiple downstream pathways necessitates the evaluation of a highly specific Pin1 inhibitor to aid in potential therapeutic drug discovery.

Formulation, preparation of niosome loaded zinc oxide nanoparticles and biological activities.

In this study, zinc oxide nanoparticles (Zn-NPs) were prepared by the green synthesis method and loaded inside niosomes as a drug release system and their physicochemical and biological properties were determined. Zn-NPs were prepared by the eco-friendly green strategy, the structure, and morphological properties were studied and loaded into niosomes. Subsequently, different formulations of niosomes containing Zn-NPs were prepared and the optimal formulation was used for biological studies. Scanning electron microscope (SEM) and dynamic light scattering (DLS) were used to investigate the morphology and size of nanoparticles. Fourier transform infrared spectroscopy (FTIR) and UV-Vis were used to confirm the synthesis of Zn-NPs. Energy dispersive X-ray spectrometer (EDS) determined the elemental analysis of the Zn-NPs synthesis solution and the crystalline structure of Zn-NPs was analysed by XRD (X-Ray diffraction). Furthermore, Zn-NPs were loaded inside the niosomes, and their structural characteristics, entrapment efficiency (EE%), the release profile of Zn-NPs, and their stability also were assessed. Moreover, its antimicrobial properties against some microbial pathogens, its effect on the expression of biofilm genes, and its anticancer activity on the breast cancer cell lines were also determined. To study the cytocompatibility, exposure of niosomes against normal HEK-293 cells was carried out. In addition, the impact of niosomes on the expression of genes involved in the apoptosis (Bcl2, Casp3, Casp9, Bax) at the mRNA level was measured. Our findings revealed that the Zn-NPs have a round shape and an average size of 27.60 nm. Meanwhile, UV-Vis, FTIR, and XRD results confirmed the synthesis of Zn-NPs. Also, the EE% and the size of the optimized niosomal formulation were 31.26% and 256.6 ± 12 nm, respectively. The release profile showed that within 24 h, 26% of Zn-NPs were released from niosomes, while in the same period, 99% of free Zn-NPs were released, which indicates the slow release of Zn-NPs from niosomes. Antimicrobial effects exhibited that niosomes containing Zn-NPs had more significant antimicrobial and anti-biofilm effects than Zn-NPs alone, the antimicrobial and anti-biofilm effects increased 2 to 4 times. Cytotoxic effects indicated that when Zn-NPs are loaded into niosomes, the anticancer activity increases compared to Zn-NPs alone and has low cytotoxicity on cancer cells. Niosomes containing ZnNPs increased the apoptosis-related gene expression level and reduced the Bcl2 genes. In general, the results show that niosomes can increase the biological effects of free Zn-NPs and therefore can be a suitable carrier for targeted delivery of Zn-NPs.

Atorvastatin's Therapeutic Potential in Atherosclerosis: Inhibiting TGF-ß-Induced Proteoglycan Glycosaminoglycan Chain Elongation through ROS-ERK1/2-Smad2L Signaling Pathway Modulation in Vascular Smooth Muscle Cells.

OBJECTIVE: According to the response-to-retention hypothesis, the inception of atherosclerosis is attributed to the deposition and retention of lipoprotein in the arterial intima, facilitated by altered proteoglycans with hyperelongated glycosaminoglycan (GAG) chains. Recent studies have elucidated a signaling pathway whereby transforming growth factor-ß (TGF-ß) promotes the expression of genes linked to proteoglycan GAG chain elongation (CHSY1 and CHST11) via reactive oxygen species (ROS) and the downstream phosphorylation of ERK1/2 and Smad2L. Atorvastatin is known to exhibit pleiotropic effects, including antioxidant and anti-inflammatory. The purpose of the present research was to ascertain the influence of atorvastatin on TGF-ß-stimulated expression of CHSY1 and CHST11 and associated signaling pathways using an in vitro model. MATERIALS AND METHODS: In this experimental study, vascular smooth muscle cells (VSMCs) were pre-incubated with atorvastatin (0.1-10 µM) prior to being stimulated with TGF-ß (2 ng/ml). The experiment aimed to evaluate the phosphorylation levels of Smad2C, Smad2L, ERK1/2, the NOX p47phox subunit, ROS production, and the mRNA expression of CHST11 and CHSY1. RESULTS: Our research results indicated that atorvastatin inhibited TGF-ß-stimulated CHSY1 and CHST11 mRNA expression. Further experiments showed that atorvastatin diminished TGF-ß-stimulated ROS production and weakened TGF-ß-stimulated phosphorylation of p47phox, ERK1/2, and Smad2L; however, we observed no effect on the TGF-ß- Smad2C pathway. CONCLUSION: These data suggest that atorvastatin demonstrates anti-atherogenic properties through the modulation of the ROS-ERK1/2-Smad2L signaling pathway. This provides valuable insight into the potential mechanisms by which atorvastatin exerts its pleiotropic effects against atherosclerosis.

Myosin light chain phosphatase is a downstream target of Rho-kinase in endothelin-1-induced transactivation of the TGF-ß receptor.

BACKGROUND: Rho-kinase (ROCK) regulates actomyosin contraction, coronary vasospasm, and cytoskeleton dynamics. ROCK and of NADPH oxidase (NOX) play an essential role in cardiovascular disease and proteoglycan synthesis, which promotes atherosclerosis by trapping low density lipoprotein. ROCK is activated by endothelin-1 (ET1) and transactivates the transforming growth factor beta receptor (TGFßR1), intensifying Smad signaling and proteoglycan production. This study aimed to identify the role of myosin light chain phosphatase (MLCP) as a downstream target of ROCK in TßR1 transactivation. METHODS: Vascular smooth muscle cells were treated with ET1 and inhibitors of ROCK and MLCP were added. The phosphorylation levels of Smad2C, myosin light chain (MLC), and MLCP were monitored by western blot, and the mRNA expression of chondroitin 4-O-sulfotransferase 1 (C4ST1) was assessed by quantitative real-time PCR. RESULTS: We examined ROCK's role in ET1-induced TGFßR1 activation. ROCK phosphorylated MLCP at the MYPT1 T853 residue, blocked by the ROCK inhibitor Y27632. ROCK also increased MLC phosphorylation and actomyosin contraction in response to ET1, enhanced by the phosphatase inhibitor Calyculin A. Calyculin A also increased C4ST1 expression, GAG-chain synthesizing enzymes. CONCLUSIONS: This work suggests that ROCK is involved in ET1-mediated TßR1 activation through increased MLCP phosphorylation, which leads to Smad2C phosphorylation and stimulates C4ST1 expression.

Paradoxical effect of Aß on protein levels of ABCA1 in astrocytes, microglia, and neurons isolated from C57BL/6 mice: an in vitro and in silico study to elucidate the effect of Aß on ABCA1 in the brain cells.

Impaired cholesterol metabolism has been reported in Alzheimer's disease. Since ABCA1 is one of the main players in the brain's cholesterol homeostasis, here we used the in-vitro and in-silico experiments to investigate the effect of Aß on ABCA1 protein levels in microglia, astrocytes, and neurons in mice. Microglia, astrocytes, and neurons were cultured and exposed to beta amyloid. ABCA1 in cell lysates was determined by Western blotting, and cholesterol efflux was measured in the conditioned media. Molecular docking, molecular dynamics simulations, and MM-GBSA analysis were conducted to gain a better understanding of the effects of Aß on ABCA1. In response to Aß, the protein levels of ABCA1 increase significantly in microglia, astrocytes, and neurons; however, its ability to enhance cholesterol efflux is diminished. Aß inhibited the function of ABCA1 by obstructing the extracellular tunnel that transports lipids outside the cell, as determined by molecular docking. MD simulation analysis validated these findings. Our results demonstrated that Aß could increase ABCA1 protein levels in various brain cells, regardless of cell type. Molecular docking, molecular dynamics simulation, and MM-GBSA studies indicate that Aß has a significant effect on the structural conformation of ABCA1, possibly interfering with its function. We believe that the conformational changes of ABCA1 will inhibit its ability to subsequently release cellular cholesterol. Aß may obstruct the extracellular tunnel of ABCA1, rendering it less accessible to proteases such as the calpain family, which may explain the increase in ABCA1 levels but decrease in its function.Communicated by Ramaswamy H. Sarma.